Fragile X syndrome (FraX) is the most common known cause of inherited mental impairment. FMR1 gene mutations, the cause of FraX, lead to reduced expression of FMR1 protein (FMRP) and increased risk for a particular profile of cognitive, behavioral and emotional dysfunction. Because of the similarity of these features to important (idiopathic) DSM-IV diagnoses, the study of individuals with FraX provides a window of understanding into disorders such as autism, social phobia, depression, and cognitive disability. The study of FraX also is a portal to the realization of innovative interdisciplinary research that spans multiple clinical and basic scientific domains. Such research provides new insights into understanding how genetic and environmental factors contribute to complex variations in typical and atypical human behavior. In this application, we describe plans to build on a unique study of individuals with FraX that has been in existence since 1992. In the first component of our research, we will continue a longitudinal study of 80 well-described individuals with FraX as they reach a critical phase of development - adolescence and young adulthood. Key cognitive, behavioral, neuroendocrinological, genetic and environmental data will be collected, and the relation of these data to functional outcome will be examined. This component of the study will represent the largest comprehensive, prospective investigation of a FraX cohort during adolescence and young adulthood. In the second component of our research, we will extend our investigation into the neurobiology of FraX using novel behavioral studies and advanced, multi-modal neuroimaging experiments to more fully elucidate brain structure, biochemistry, connectivity and function underlying aberrant cognition and behavior. Within the context of the second aim, we also will examine the efficacy of brief intervention trials focused on improving executive function and social behavior. These pilot trials will utilize innovative behavioral and real-time functional magnetic resonance imaging (rtfMRI) strategies and are designed to generate preliminary data to guide the development of new FraX specific treatments in the future. The Center for Interdisciplinary Brain Sciences Research (CIBSR), directed by the PI, Dr. Allan Reiss, represents one of only a handful of sites in the world that has made a long-term commitment to comprehensive, interdisciplinary research on FraX. The work performed in the CIBSR is particularly focused on applied investigation that will provide new knowledge, methods and tools to improve the lives of persons with FraX and their families. [unreadable] [unreadable] [unreadable]